1. Field of the Invention
This invention relates generally to control of the mechanism by which epithelial cells become malignant and more specifically to treatment and diagnosis of carcinoma.
2. Description of Related Art
The development and phenotypic expression of overt cellular malignancy has long been associated with changes in the cells' genome. In January 1982 (Bissell, M. J., Hall, H. G., and Parry, G.; "How Does the Extracellular Matrix Direct Gene Expression?", J. Theor. Biol, 99: 31-68, 1982) Bissell et al. reported an epithelial cell model wherein the extracellular matrix (ECM) affected chromatin structure and thereby gene expression through its connection to the nuclear matrix and cytoskeleton. A cell's ability to synthesize competent ECM was in turn predicted to be a function of the chemical and mechanical properties of the culture milieu. Thus a dynamic reciprocity between the genome and the ECM was postulated.
Petersen, Bissell, and others (Petersen et al., Proc. Natl. Acad. Sci. USA, 89:9064-9068, 1992) developed an assay system to distinguish the growth and differentiation pattern of normal and malignant human breast epithelial cells. Using a reconstituted basement membrane (BM) they were able to culture normal human breast epithelial cells and corresponding carcinoma cells. They demonstrated, for the first time, that normal cells re-expressed their in-vivo differentiated morphology in culture. Single cells formed multicellular spherical colonies with a final size similar to true acini in situ. These normal colonies exhibited many other attributes, normally seen only in situ: a central lumen surrounded by polarized luminal epithelial cells, three dimensional cellular architecture, biochemical expression consistent with mammary epithelial cell biology, and growth inhibition. In contrast, the carcinoma cells and cells from biopsy specimens had growth rates that were unaffected in the reconstituted basement membrane and they continued to express the undifferentiated phenotype typical of the tumor state.
Streuli and Bissell reported in (J. Cell Biol, 115:1383-1395, 1991) that in mouse mammary epithelial cells (MEC) the .beta..sub.1 integrin receptor played a key role in transmitting signals necessary for growth, differentiation, and survival, between the extracellular matrix and the cell interior. Observations by Boudreau et al. (Science, 267:891-893 Jan. 10, 1995) strengthened that observation and Howlett et al. (Howlett, A. R., Bailey, N., Damsky, C., Petersen, O. W., and Bissell, M. J.; "Cellular Growth and Survival are Mediated by Beta-1 Integrins in Normal Human Breast Epithelium But Not in Breast Carcinoma, "J. Cell Sci., 108: 1945-1957, 1995) extended those observations to include a phenotypically normal cell line of human MEC. Normal mouse MECs cultured in a reconstituted basement membrane were protected from apoptosis. If the ability of the normal cells' .beta..sub.1 integrin receptor to interact with the basement membrane was blocked with a specific antibody, the cells died. These results supported the notion that .beta..sub.1 integrin receptors are important for competent interaction between the ECM and the cell and are necessary to maintain the normal differentiated state of MECs.
In the Japanese Journal of Cancer Research, 83:1317-1326, December 1992, Fujita et al. reported that a newly established anti-human .beta..sub.1 subunit monoclonal antibody inhibited the invasion and metastasis of human bladder carcinoma cell and human gastric carcinoma cells in nude mice. They postulated that .beta..sub.1 integrins play an important role in tissue attachment, migration, invasion and metastasis of human carcinoma cells.